17alpha, 21-oxides of 1, 4-pregnadiene compounds



170:,21-0XIDES F 1,4-PREGNADIENE v COMPOUNDS George A. Bailey, Roselle,and Ralph F. Hirschmaun, Westfield, N. J., assignors to Merck & -Co.,Inc., Rahway, N. J., a corporation of New Jersey N0 Drawing. ApplicationSeptember 20, 1956 Serial No. 610,888

4 Claims. (Cl. 2 60239.55)

This invention relates to steroids and particularly to novel compoundshaving cortisone-like activity.

According to the present invention, there are produced novell7a,21-oxides of 1,4-pregn'adiene compounds having cortisone-likeanti-inflammatory activity. These are 1lfi-hydroxy-S,ZO-diketo-1,4-pregnadiene-l 7a,2l-oxide and3,1l,ZO-triketo-l,4-pregnadiene-17cz,2l-oxide. These compounds may berepresented by the following structural formula:

where R is selected from the (0:) and hydroxyl group con'sisting of ketoThe therapeutic activity of the l7oc,2l-OXidS according surprising inview of the fact that the to this invention is compounds 1lfi-hydro-xy-3,20-diketo-4-pregnene-l7a,2loxide (hydrocortisone oxide)and 3,11,20-triketo-4-pregbe prepared by reaction of the corresponding21-hal0 compounds, where the 21-halo atom has an atomic Weight In theabove equation, X represents either chlorine, bromine, or iodine, and Yrepresents a cationic element or radical having a valence n. The 2l-iodosteroid compounds are preferred, although the 21-chloroand 21- 2,855,915Patented"De'c. 23, .1358

Example 1 A mixture of 25.9 g. of 21-iodo-1lfi,17a-dihydroxy-3,20-diketo-1,4-pregnadiei1e and 66.8 g. of silver carbonate in 500 ml.of acetonitrile are refluxed with constant The product is filtered, anda fin'ely divided-diatomaceous earth 'filter aid is present tofacilitate filtration. The-filter Washed with hot acetonitr'ile, and'the combined filtrate and Washes are treated charcoal. The'acetonitrile'is evaporated'and '500 m1. of chloroform are added todissolve the crude steroid 17,21- oxide product. The solution is passedthrough a column containing 520 g. of alumina to adsorb theoxide,-whi'ch v is eluted with 4 liters of chloroform. The chloroformmoved from the vessel.

is evaporated, and the product, 1lfi-hydroxy-3,20-diketo-1,4-pregnadiene-17u,21--oxide (prednisolon'e oxide) is recrystallizedfrom an acetone-n-hexane mixture. The melting point is 242 to 244 C.Other properties:

Analysis.F-ound: c, 73.84; H, 7.74.

Example -2 A mixture of 1.379 liters of phosphoric acid and 3.36 kg. oftrisilverphosphate is prepared in a 30-gallon stainless steel vesselwith vigorous agitation by means of Then 42 liters of acetonitrile areand a flowing nitrogen atmosphere is introduced in place 1.05 kg. of2l-iodo- 11B,17u-dihydroxy-3,20-diketo-1,4-pregnadiene. The mixture isrefluxed for 1% hours in a'nitrogen atmosphere and then is cooled to 25to 30 C. Then 7 kg. of ice and 6.1 liters of water are added to thevessel and the slurry is re- The vessel is rinsed with 6 liters ofacetonitrile in three equal portions and the rinsings are combined withthe slurry.

The acetonitrile is evaporated under high vacuum at a temperature belowC. leaving water until the washings contam no ultra-violet absorbingmaterial. The cake, which weighs approximately 10.5 kg., is extractedwith acetone tals.

" mation of well-defined crystals.

ether (boiling point range "phosphoric acid mixture. 3,11,20-triketo-1,4pregnadiene-Hall-oxide.

is cooled to 5 C.,filtered, and washed with two portions of water of twoliters each. The filter cake is dried.

The dried material is slurried in liters of benzene and the insolublematerial is filtered off. The filter cake is washed with benzene whichis added to the filtrate. The

benzene solution is then passed through a. column of 20 pounds ofchromatographic grade alumina. The column is eluted with 30 g. of amixtureof 50% by volume ben zene and 50% chloroform. The eluate isspot-checked periodically for the presence of crystalline material andthe addition of benzene-chloroform eluant is stopped when no crystallinematerial is observed. The eluant is concentrated to 7 liters,transferred to a 12-liter flask, and concentrated to near dryness withthe formation of crys- The crystals are dissolved in 2 liters of'acetoneand 15 g. of decolorizing charcoal are'added and the lurry is filteredand washed with acetone. The filtrate and washings are concentrated to1.8 liters with the for- Two liters of petroleum 60 to 70) are addedslowly and the mixture is cooled to 5 C. and filtered. The filter cakeconstitutes the first crop of crystals and the yield is 34.7 g. of pure3,20-diketo-lIB-hydroxy-lA-pregnadiene-17a,21-oxide. A second crop ofproduct weighing 10.2 g. is obtained by concentrating the mother liquidtoi500 ml. adding 2 liters of diethyl ether and cooling.

Example 3 The procedure of Example 2 is followed except that anequivalent quantity of2l-iodo-l7u-hydroxy-3,l1,20-triketo-1,4-pregnadiene is reacted with thesilver phosphate- The product recovered is While the foregoing inventionhas been described with reference to specific details and embodimentsthereof, it is understood that the scope of this invention is measuredonly by the scope of the appended claims.

What is claimed is: V

1. A compound having the formula where R is selected from the groupconsisting of keto and p-hydroxyl. r

2. 1,4-pregnadiene-*01-3,20-dione-l7u,2l-oxide.

3. 1,4-pregnadiene-3,1l,20-trione-l7a,2l-oxide.

4. A process for preparing a compound having a formula selected from thegroup consisting of where R is selected from the group consisting ofketo and p-hydroxyl, which comprises reacting the corresponding compoundhaving the formula ClH2X =0 ---OH where X is a halogen having an atomicweight of at least 35, with a compound selected from the groupconsisting of inorganic silver salts, silver oxide, and silverhydroxide, and recovering the pregnene-l7a,21-oxide from thewater-insoluble products.

No references cited.

1. A COMPOUND HAVING THE FORMULA